9 Investigator Commentary: Phase Ib Study of Pembrolizumab in Classical HL After Disease Progression on Brentuximab VedotinThis study evaluated the effect of pembrolizumab in a cohort of patients with heavily pretreated HL. In the KEYNOTE-013 trial, pembrolizumab is also being investigated in patients with other hematologic cancers such as myelodysplastic syndromes. In HL, amplification of 9p24.1 and Epstein-Barr virus infection contribute to overexpression of PD-L1 and PD-L2. Also, much cross talk occurs between Reed-Sternberg cells and cells in the surrounding inflammatory infiltrate, which makes HL a tumor that is amenable to immunotherapy. Pembrolizumab, like nivolumab, causes dual blockade of both PD-L1 and PD-L2.An interesting aspect of our study is that of the 29 patients evaluable to date, 70% are still on treatment. The median time to response to pembrolizumab was 12 weeks, which is longer than that with chemotherapy. With checkpoint inhibitors, most of the patients who achieve a complete response do so at the first restaging. However, patients’ conditions improve with time — for example, stable disease can be converted to partial response with time. You don’t want to stop therapy too early, provided that there are no new sites of disease.Interview with Craig Moskowitz, MD, January 6, 2015

10 Investigator Commentary: Phase Ib Study of Pembrolizumab in Classical HL After Brentuximab Vedotin FailureThe data with PD-1 inhibitors in hematologic cancers, particularly HL, are exciting. The overall response rate for patients with HL treated with pembrolizumab was 66%. As you can see in the waterfall plot, a majority of the patients derive a benefit from this agent.A number of reasons explain the significant likelihood of benefit with PD-1 inhibitors in HL. The rich inflammatory infiltrate suggests that immune cells are present. The majority of the cells in the tumor microenvironment have a Th1 phenotype, suggesting that those cells are armed and ready for action. The ligands for PD-1, namely PD-L1 and L2, are highly expressed on Reed-Sternberg cells. Alterations in the 9p24.1 chromosome that result in the overexpression of PD-L1 and L2 are commonly seen in relapsed HL. Infection with the Epstein-Barr virus may also upregulate PD-L1 and PD-L2. Even though immune cells are present, they are ineffective. When the interaction between PD-1 and its ligands is blocked, these immune cells can be reactivated and can target the malignant cells.I believe this is a very promising approach for the future.Interview with Stephen M Ansell, MD, PhD, January 20, 2015